The SCID-hu-PBL model was employed to explore the immunologic and virologic effects of different immune-based therapies on the course of human immunodeficiency virus type-1 (HIV-1) infection as well as to provide a model that could be used to dissect the immunologic aspects of the human immune response to HIV, particularly in patients with stable disease. This model involves reconstitution of 8- to 12-week-old SCID mice with fresh peripheral blood mononuclear cells from human donors. The SCID-hu-PBL model of HIV-1 infection was used to demonstrate that FddA has significant antiviral activity that is consistently superior to ZDV when administered either therapeutically or prophylactically in this experimental system. The adoptive transfer of primed lymphocytes from a gp160-immunized donor coupled with the infusion of high-titer anti-gp160 antibody appears to afford little or no protective immunity against subsequent challenge with HIV-1 in this system. In the latest series of experiments, the model was modified to include direct reconstitution of SCID mice with PBLs from HIV-1-infected donors with stable clinical disease rather than through infection by secondary challenge with purified viral stocks. Intraperitoneal injection of harvested mononuclear cells from infected patients in this hu-HIV/PBL-SCID modification led to successful engraftment in 84% of mice, as confirmed by both PCR detection of human cells and by detection of human Ig antibody production, and caused no diminution in the number of human mononuclear cells harvested by peritoneal lavage relative to control mice engrafted with uninfected cells. Virus was readily recoverable in 98% of engrafted mice using either PCR or co-cultivation methods. Reconstituted hu-HIV/PBL-SCID mice that were untreated sustained a 75% decrease in human CD4+ lymphocyte recovery in peritoneal wash relative to control mice, whereas treatment with the nucleoside analogue FddA both significantly reduced CD4+ cell depletion as well as inhibited viral recovery. Boosting circulating human Ig antibody levels through injection of purified antibody derived from the donor's plasma, or treating mice with a series of human IL-2 injections, did not influence either CD4+ cell survival or viral recovery. In contrast, administration of 10 mg/kg of monoclonal antibody to human tumor necrosis factor-alpha significantly improved CD4+ cell count survival in reconstituted animals.